Normal cornification of skin causes a phenomenon known as “denucleation”, whereby the nuclei of keratinocytes disappear. Epidermal keratinocytes proliferate in the basal layers, and migrate to the upper layers where they mature into the stratum corneum. However, in rough skin that has not undergone normal cornification, as a result of skin diseases such as psoriasis or atopic dermatitis, the nuclei of the cornified cells remains in a undigested state, whereby the cornified cells are found in the stratum corneum in an immature state in which nuclei is retained. This condition is known as “parakeratosis”. Although the phenomenon of parakeratosis has long been recognized, the mechanism by which parakeratosis occurs, and the biochemical markers for it, have been unknown.
Squamous cell carcinoma antigen (SCCA), an antigen extracted from squamous carcinoma cells, is found at high concentration in blood from patients suffering from squamous cell carcinoma of the uterine cervix, lungs, esophagus or skin, and it is commonly used for diagnosis of squamous cell carcinoma (Kato H. et al. Cancer 40:1621-1628 (1977); Mino N. et al. Cancer 62: 730-734 (1988)). In particular, SCCA blood level positively correlates with squamous cell carcinoma progression stage, malignancy and tumor size, and it is an especially effective cancer marker not only for early detection of cancer but also for evaluating treatment effects and diagnosing the risk of recurrence.
SCCA is also known to be overexpressed in the upper layer of psoriatic epidermis (Takeda A. et al, J. Invest. Dermatol. 118(1): 147-154 (2002)). Psoriasis is a type of skin disease that can take the form of chronic, relapsing inflammatory parakeratosis characterized by abnormal proliferation and differentiation of epidermal cells and infiltration of inflammatory cells. Onset of psoriasis is attributed both to genetic factors and to various environmental factors (Hopsu-Havu et al. British Journal of Dermatology 109: 77-85 (1983)).
There are two kinds of genes, i.e., SCCA-1 and SCCA-2, situated in tandem on chromosome 18q21.3 which code for SCCA. The proteins SCCA-1 and SCCA-2 encoded by these genes are of approximately 45,000 in molecular weight, and exhibit high homology of 95% on the nucleic acid level. The SCCA proteins belong to the ovalbumin-serine protease inhibitor (ov-serpin) family. The ov-serpin family has unique characteristics among the serpin superfamily. Serpins are generally secreted and act extracellularly, but ov-serpins are protease inhibitors that act primarily intracellularly.
SCCA-1 is a papain-like cysteine protease inhibitor while SCCA-2 is a chymotrypsin-like serine protease inhibitor, and despite their high homology, their differing amino acid sequences at the reactive site are responsible for producing different behavior (Schick et al. J. Biol. Chem. 272(3): 1849-55 (1997)). It has been known that SCCA-1 and SCCA-2 are highly expressed in diseases such as psoriasis or by UV irradiation, but their association with skin condition has not been elucidated.